This R21 proposal is designed to investigate the efficacy of Meriva, a unique formulation of the neutraceutical curcumin with enhanced absorption properties, to reduce chemotherapy and radiotherapy (XRT)-associated activation of the nuclear factor-kappa B (NF-kB) pathway in circulating peripheral blood mononuclear cells (PBMCs) in women treated for breast cancer. As many as 60% of breast cancer patients who receive radiation are known to develop fatigue, with about 30% suffering persistent fatigue several months to years after treatment completion. Fatigue therefore represents a persistent problem, even after successful completion of treatment for breast cancer. The physical, psychological, and molecular mechanisms by which patients develop fatigue are poorly understood and are most likely multi-factorial. However, one pathway that has received considerable attention is nuclear factor-kappa B (NF-kB). Our work has shown that NF-kB pathway activity in circulating immune cells is associated with the development of fatigue in patients treated with radiation. Importantly, we have also found that patients most at risk for persistent fatigue and NF-kB pathway activity are those who have received both chemotherapy and radiation for their breast cancer. We therefore believe that NF-kB represents an important target for the treatment of breast cancer-related fatigue. Curcumin, the principal component of turmeric and derived from the plant curcumin longa, has been shown to impact a number of molecular signaling pathways, including NF-kB. Although curcumin has been a food additive for centuries and is widely consumed as a neutraceutical, the effectiveness of orally administered curcumin to modulate NF-kB is believed to be severely limited by the poor absorption or curcumin. Meriva is a curcumin formulation that includes phosphatidylcholine. The combination of phosphatidylcholine with curcumin has been shown to enhance the absorption of curcumin compared to curcumin alone. As a result, Meriva represents an exciting way by which to reduce NF-kB activation and fatigue in women treated with chemotherapy and radiation for breast cancer. To date Meriva has shown considerable promise in the context of several disorders, including type-2 diabetes, osteoarthritis and chronic anterior uveitis. However, the effectiveness of Meriva to prevent and reverse fatigue in the context of breast cancer is yet to be evaluated. This proposal is designed to address this. Of note, our team members at Emory have already received an IND from FDA for the studies proposed. The major hypothesis of the current proposal is that Meriva will reduce inflammatory activation measured at the level of NF-kB as well as downstream proinflammatory cytokines in women treated for breast cancer. We also predict that Meriva will decrease fatigue symptoms, in a manner that is associated with reduced inflammation. Besides demonstrating that Meriva positively affects fatigue in women after breast cancer treatment, studies proposed here will also establish a mechanism for action for curcumin on fatigue.